Separation and purification method for thiourea-containing polymer in demethylation compound

Abstract

The invention discloses a method for separating and purifying a thiourea polymer in a demethylation compound, which comprises the following steps: mixing the thiourea polymer in a demethylation product with water, heating the obtained mixed solution to 80-90 DEG C, and keeping the temperature for 4-6 hours, so that the thiourea polymer impurity in the product is dissolved in hot water; carrying out solid-liquid separation on the obtained solid-liquid mixture to obtain a solid substance demethylated compound, wherein the demethylated substance does not contain the thiourea polymer; the water phase is cooled to the room temperature, a product is separated out, another solid phase is the thiourea polymer, and the mass percent of the thiourea polymer in the demethylation substance is smaller than 0.05%. According to the method, the demethylation compound and the impurity thiourea polymer are separated and purified by utilizing the characteristics that the solubility of the demethylation compound in water is small, and the thiourea polymer is dissolved in water. Experimental results show that the method provided by the invention can effectively improve the purity and content of demethylated substances, and is low in production cost, green and environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the purification of chemical products, in particular to a method for separating and purifying a demethylated compound containing thiourea polymer. BACKGROUND

[0002] Desmethylvenlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) produced by the pharmaceutical subsidiary of the company, for the treatment of major depressive disorder (MDD) in adults. It is an active metabolite of the antidepressant venlafaxine, the trade name of "Pristiq", which was approved by the FDA on February 29, 2008.

[0003] At present, many desmethylvenlafaxine are prepared from venlafaxine as starting material. Such routes can generally obtain high yield. Thiourea is often used for demethylation in organic synthesis, especially in the demethylation of methyl ether or methyl amino group, which shows unique activity. Therefore, the use of thiourea for demethylation of venlafaxine is mild, efficient and economical. For example, Chinese patent 200980137796.2 discloses that after mixing thiourea and venlafaxine, solid precipitates are obtained, and then filtered to obtain crude desmethylvenlafaxine. Then the crude desmethylvenlafaxine is added to methanol, refluxed and cooled. The crystalline pure desmethylvenlafaxine is filtered out.

[0004] The above route will have residual thiourea polymer in the crystalline pure desmethylvenlafaxine filtered out in mass production, which is generally not easy to find and affects the quality of the subsequent product. Because the demethylation reaction under the condition of thiourea often produces a large amount of by-product thiourea polymer, which is not easy to remove and easy to remain. The thiourea polymer leads to low product content, poor quality, and large loss in separation and purification. In view of the above shortcomings, it is urgent to develop a simple, green and efficient separation and purification technology, which can effectively improve the product quality and reduce the product loss. SUMMARY

[0005] The present application provides a separation and purification method for removing thiourea polymer, and the main product obtained by the separation and purification technology provided by the present application has good quality and low cost.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical scheme:

[0007] The present application provides a separation and purification method for removing thiourea polymer, and the main product obtained by the separation and purification technology provided by the present application has good quality and low cost.

[0008] (1) adding a demethylated compound containing a large amount of thiourea polymer into a solvent to obtain a primary solid-liquid mixture;

[0009] (2) heating and stirring the obtained primary solid-liquid mixture at 80-90℃ to form a slurry;

[0010] (3) stirring and heating the mixture for 4-6 hours to form a slurry, and then separating the solid and the liquid to obtain a demethylated product, and cooling the filtrate to precipitate a solid, which is a thiourea polymer.

[0011] In the present application, the demethylated compound in step (1) is a demethylated venlafaxine product.

[0012] In the present application, the demethylated venlafaxine product in step (1) comprises desmethyl venlafaxine, a thiourea polymer, methanol, inorganic salts, polyethylene glycol, and water. The present application does not have a special limitation on the impurities, which are well known in the art.

[0013] In the present application, the mass percentage of the thiourea polymer in the demethylated compound in step (1) is less than 20%, preferably less than 10%.

[0014] In the present application, the solvent in step (1) is water.

[0015] In the present application, the weight ratio of the demethylated compound to the solvent in step (1) is 1:(8-10), preferably 1:(10-12), and more preferably 1:(12-15).

[0016] In the present application, the stirring and slurry-forming temperature in steps (2) and (3) is 80-90℃, preferably 85-95℃.

[0017] In the present application, the stirring and slurry-forming speed in steps (2) and (3) is 100-200 rpm, preferably 200-300 rpm, which is beneficial to dispersing the thiourea polymer into hot water.

[0018] In the present application, the reaction time in step (3) is 4-6 hours, preferably 5-6 hours, which is beneficial to the hot dissolution of the thiourea polymer into water.

[0019] In the present application, the solid-liquid separation method in step (3) is centrifugation, suction filtration, or pressure filtration.

[0020] In the present application, the mass percentage of the thiourea polymer in the demethylated product in step (3) is ND-0.05%.

[0021] The present application does not have a special limitation on the mixing of the solid substances and the solvent in the primary solid-liquid mixture, and the mixing should be sufficient to form a uniform mixture.

[0022] The source of the demethylated compound is not particularly limited in the present application, and a source of the demethylated compound known to those skilled in the art can be used, for example, a demethylation reaction and other waste residues that produce by-product thiourea polymers.

[0023] The present application has the beneficial effect that, when performing scale-up production, thiourea is used to perform a demethylation reaction, and thiourea polymers are easily produced, which are not easy to remove completely, resulting in unqualified products, and further resulting in material scrap, while the present method can effectively control the residual thiourea polymers, ensuring product quality. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 is an HPLC spectrum of a demethylated venlafaxine product;

[0025] Figure 2 is an HPLC spectrum of a demethylated product. DETAILED DESCRIPTION

[0026] In order to further illustrate the present application, the thiourea polymer recovery method provided by the present application is described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application. Obviously, the described examples are only some of the examples of the present application, not all. Based on the examples in the present application, all other examples obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present application.

[0027] Example 1

[0028] 100 g of demethylated venlafaxine product was taken for sampling and testing, and the external standard content of thiourea polymers in the waste residue was 20% (i.e. about 20 g of thiourea polymers in 100 g of demethylated venlafaxine product); the obtained demethylated venlafaxine product and 1000 g of water were mixed and heated to 80-90°C, and the reaction was kept at 150 rpm for 4-6 hours, and then hot filtration was performed to obtain a demethylated product without thiourea polymers. The purity was >99.0%.

[0029] Example 2

[0030] 100 g of demethylated venlafaxine product was taken for sampling and testing, and the external standard content of thiourea polymers in the waste residue was 15% (i.e. 15 g of thiourea polymers in 100 g of demethylated venlafaxine product); the obtained demethylated venlafaxine product 100 g and 900 g of water were mixed and heated to 80-90°C, and the reaction was kept at 200 rpm for 4-6 hours, and then hot filtration was performed to obtain a demethylated product without thiourea polymers. The purity was >99.0%.

[0031] Example 3

[0032] The sample of 100 g of demethylated venlafaxine product is detected to obtain the external standard content of thiourea polymer in the waste residue, which is 10% (i.e. 10 g of thiourea polymer in 100 g of demethylated venlafaxine product); the obtained demethylated venlafaxine product and 1200 g of water are mixed and heated to 80-90°C, and the reaction is carried out at a rotation speed of 150 rpm for 4-6 hours, and then the demethylated product without thiourea polymer is obtained by hot filtration, and the purity is >99.0%.

[0033] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for separating and purifying thiourea polymers contained in demethylated compounds, characterized in that, Includes the following steps: (1) Add the demethylated compound containing a large amount of thiourea polymer to the solvent and mix to obtain a primary solid-liquid mixture; (2) Heat the obtained primary solid-liquid mixture to 80-90℃ and stir to make a pulp; (3) Stir and slurry the heated mixture and keep it warm for 4 to 6 hours. Then, perform solid-liquid separation to obtain the demethylated product. The solid precipitated from the filtrate after cooling is a thiourea polymer.

2. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The demethylated compound in step (1) is a new product of the demethylation Venla process.

3. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 2, characterized in that, The components of the demethylated venlafaxine product in step (1) include demethylated venlafaxine, thiourea polymer, methanol, inorganic salt, polyethylene glycol, and water.

4. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The mass percentage of thiourea polymer in the demethylated compound in step (1) is less than 20%.

5. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, In step (1), the weight ratio of the demethylated compound to the solvent is 1:(8-10), and the solvent is water.

6. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The stirring and pulping temperature in steps (2) and (3) is 80-90℃.

7. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The stirring and slurrying speed in steps (2) and (3) is 100-200 rpm.

8. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The reaction time in step (3) is 4 to 6 hours.

9. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The solid-liquid separation method in step (3) is centrifugation, vacuum filtration or pressure filtration.

10. The method for separating and purifying thiourea polymers from demethylated compounds according to claim 1, characterized in that, The mass percentage of thiourea polymer in the demethylated product in step (3) is ND-0.05%.

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